Trialkylamine derivative and ameliorant for digestive tract movement containing the same

ABSTRACT

A trialkylamine derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof: ##STR1## wherein R 1  and R 2  may be the same or different from each other and each represents lower alkyl; 
     R 3 , R 4  and R 5  may be the same or different from one another and each represents hydrogen, lower alkyl, lower alkoxy, lower alkoxycarbonyl or halogen; 
     R 6  and R 7  may be the same or different from each other and each represents hydrogen or lower alkyl; 
     R 8  represents hydrogen, lower alkyl, lower alkoxy or halogen; 
     X represents oxygen, sulfur, --CH═N-- or --CH═CH--; 
     Y represents oxygen, sulfur, methylene, N--R 11  (wherein R 11  represents lower alkyl), SO or SO 2  ; 
     Z represents --OCO(CH 2 ) p  ˜ or --OCH 2  (CH 2 ) p  ˜ (wherein p represents a number of 0 to 4 and symbol ˜ represents the linkage with a benzene ring); and 
     m and n represent each a number of 0 to 3 and the sum of m and n is 3 or less, provided that the case where m is 0, n is 1 or 2, R 1  and R 2  represent each methyl, X represents --CH═CH--, Y represents --CH 2  --, and Z represents --O--CO˜ is excluded. These compounds have an excellent activity of ameliorating for gastrointestinal motility and hence are widely utilized in the treatment of gastrointestinal diseases.

TECHNICAL FIELD

The present invention relates to trialkylamine derivatives useful in themedical field, and more particularly, to trialkylamine derivativescapable of significantly ameliorating the digestive tract movement(gastrointestinal motility), intermediates for preparing thederivatives, and ameliorants for gastrointestinal motility.

BACKGROUND ART

Hitherto, trimebutine maleate has been primarily used as an ameliorantfor gastrointestinal motility.

The trimebutine maleate has wide utility due to its two-face activitiesof promoting and suppressing the gastric movement. However, it is notnecessarily satisfactory in that relatively large amounts, i.e., 300 mgper day of dose are required.

To avoid this disadvantage, studies have been conducted in search forameliorants for gastrointestinal motility which can replace trimebutinemaleate.

For example, (1-dimethylaminoindan-1-yl)methyl ester of substitutedbenzoic acid and(1-dimethylamino-1,2,3,4-tetrahydronaphthalen-1-yl)methyl ester ofsubstituted benzoic acid are reported to have anticonvulsive activity,antiulcer activity and local anesthetic activity ("ScientiaPharmaceutica" vol. 56, pp. 243-250, 1988).

These, however, do not necessarily provide sufficient amelioratingactivity on the gastrointestinal motility.

Accordingly, development of drugs which possess more strongerameliorating activity on the gastrointestinal motility has still beendesired.

The present inventors have carried out earnest studies under thementioned circumstances, and have found that a specified trialkylaminederivatives exhibit excellent ameliorating activity on thegastrointestinal motility leading to completion of the invention.

DISCLOSURE OF THE INVENTION

According to the present invention, there is provided trialkylaminederivatives represented by the formula (1) or pharmaceuticallyacceptable salts thereof: ##STR2## wherein R¹ and R² may be the same ordifferent from each other and each represents lower alkyl;

R³, R⁴ and R⁵ may be the same or different from one another and eachrepresents hydrogen, lower alkyl, lower alkoxy, lower alkoxycarbonyl orhalogen;

R⁶ and R⁷ may be the same or different from each halogen;

R⁶ and R⁷ may be the same or different from each other and eachrepresents hydrogen or lower alkyl;

R⁸ represents hydrogen, lower alkyl, lower alkoxy or halogen;

X represents oxygen, sulfur, --CH═N-- or --CH═CH--;

Y represents oxygen, sulfur, methylene, >N--R¹¹ (wherein R¹¹ representslower alkyl), >SO or >SO₂ ;

Z represents --OCO(CH₂)_(p) ˜ or --OCH₂ (CH₂)_(p) ˜ (wherein prepresents a number of 0 to 4 and symbol ˜ represents the linkage with abenzene ring); and

m and n represent each a number of 0 to 3 and the sum of m and n is 3 orless, provided that the case where m is 0, n is 1 or 2, R¹ and R²represent each methyl, X represents --CH═CH--, Y represents --CH₂ --,and Z represents --O--CO˜ is excluded.

The present invention also provides aminoalcohol derivatives representedby the formula (2) or salts thereof: ##STR3## wherein R¹, R², R⁶, R⁷,R⁸, X, Y, m and n have the same meaning as defined hereinbefore,provided that the case where X represents --CH═CH--,

Y represents --CH₂ --,

m is 0 and

n is 1 or 2 is excluded.

The present invention further provides ameliorants for gastrointestinalmotility containing, as their active ingredients, trialkylaminederivatives represented by the formula (1): ##STR4## wherein R¹, R², R³,R⁴, R⁵, R⁶, R⁷, R⁸, X Y, Z, m and n have the same meaning as definedhereinbefore or pharmaceutically acceptable salts thereof.

In the above formulae, the term "lower" means that the number of carbonatoms is 1 to 4, and the term "halogen" means fluorine, chlorine,bromine and iodine.

BEST MODE FOR CARRYING OUT THE INVENTION

The trialkylamine derivatives (1) according to the present invention canbe prepared as follows:

First, aminoalcohol derivatives (2), which are the intermediates in thepreparation of trialkylamine derivatives (1) of the present invention,are prepared, for example, by the following process. The reaction schemeis shown below: ##STR5## wherein R⁹ represents lower alkyl, X, Y, R¹,R², R⁶, R⁷, R⁸, m and n have the same meaning as defined hereinbefore.

In detail, the amino acid compound (5) is first esterified to obtaincompound (6) by a conventional method, and the amino group of thecompound (6) is dialkylated to obtain an ester (7), followed by reducingthe ester (7) to produce amino alcohol derivative (2). The reduction iscarried out in a solvent and in the presence of a reducing agent at -30°to 80° C. Examples of preferable solvents include ether-series solventssuch as diethylether, tetrahydrofuran and dioxane; alcohol-seriessolvents such as methanol, ethanol, propanol, isopropanol, butanol,isobutanol, sec-butanol and tert-butanol, and mixtures of ether-seriessolvents and alcohol-series solvents. Examples of preferable reducingagents include suitable selections from hydride-series reducing agentssuch as lithium aluminum hydride, sodium borohydride, lithiumtriethylborohydride, aluminum diisobutyl hydride, lithium borohydrideand diborane.

Among the aminoalcohol derivatives (2), compounds containing a sulfuratom as Y can be coverted to sulfoxides or sulfones by oxidizing thecompounds in accordance with a conventional method.

It is preferred that the oxidizing agents be metachloro perbenzoic acid,hydrogen peroxide, sodium periodate, peroxosulfates and the like.

Among the trialkylamine derivatives (1) of the present invention, thosecontaining a group --O--CO˜ (˜ has the same meaning as defined above) asZ can be prepared by reacting the aminoalcohol derivatives (2), whichare the intermediates of the process, with carboxylic acid compoundsrepresented by the formula (3): ##STR6## wherein R³, R⁴, and R⁵ have thesame meaning as defined above or their reactive derivatives such as acidhalogenides, acid anhydrides, mixed acid anhydrides and active esters.

When the reactive derivatives of carboxylic acids (3) are employed, thereaction is performed in a solvent and in the presence or absence of abasic compound at -30° to 100° C.

No particular limitation is imposed on the solvents as long as they donot adversely affect the reaction. Examples of preferable solventsinclude ether-series solvents such as diethylether, tetrahydrofuran anddioxane; halogenated hydrocarbon-series solvents such asdichloromethane, dichloroethane, chloroform and carbon tetrachloride;aromatic hydrocarbon-series solvents such as benzene, toluene andxylene; acetonitrile, dimethylformamide, dimethylsulfoxide and water.Examples of preferable basic compounds include trialkylamine, pyridine,alkali metal carbonate, alkali metal hydrogen-carbonate and alkali metalhydroxide.

When the carboxylic acid compounds (3) are used in the form of freecaroxylic acids, it is preferred to use a condensing agent. Examples ofpreferable condensing agents include carbodiimides such as N,N'-dicyclohexylcarbodiimide,N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide and its hydrochloride andcarbonyldiimidazole.

Among the compounds (1) of the present invention, those containing--O--CH₂ ˜ (wherein ˜ has the same meaning as defined above) as Z can beprepared by reacting aminoalcohol derivatives (2) with benzyl compoundsrepresented by the formula (4): ##STR7## wherein W represents a reactiveresidue and R³, R⁴ and R⁵ have the same meaning, respectively.

Examples of the reactive residue represented by W in the benzylcompounds (4) include halogen, methanesulfonyloxy, alkylsulfonyloxy,p-toluenesulfonyloxy and arylsulfonyloxy.

The above reaction is carried out in a solvent and in the presence orabsence of a basic compound at 0° to 100° C. No particular limitation isimposed on the solvents useful in the present invention as long as theydo not adversely affect the reaction. Examples of preferable solventsinclude ether-series solvents such as diethylether, tetrahydrofuran anddioxane; aromatic hydrocarbon-series solvents such as benzene, tolueneand xylene; dimethylformamide and dimethylsulfoxide. Examples ofpreferable basic compounds include alkali metal hydride, alkali metalalkoxide and alkali metal hydroxide.

Compounds having a sulfur atom as Y in the compounds (1) of the presentinvention can be oxidized to sulfoxides or sulfones by conventionalmethods.

Preferable examples of the oxidizing agents include metachloroperbenzoicacid, hydrogen peroxide, sodium periodate and peroxosulfates.

Examples of the pharmaceutically acceptable salts of the compounds (1)of the present invention include inorganic acid salts such ashydrochlorides, hydrobromides, sulfates and phosphates and organic acidsalts such as succinates, maleates, fumarates, tartrates, oxalates,methanesulfonates and paratoluenesulfonates.

Since the compounds (1) according to the present invention possessasymmetric carbon atoms, the compounds may have optical isomers orstereochemical isomers. The present invention encompasses these isomers,too.

The compounds (1) according to the present invention or theirpharmaceutically acceptable salts have an action of amelioratinggastrointestinal motility.

In order to formulate ameliorants for gastrointestinal motility from thecompounds (1) of the present invention or their pharmaceuticallyacceptable salts, the compounds are blended with pharmaceuticallyacceptable adjuvants and prepared to take suitable forms for oral-routeadministration or non-oral route administration.

In the manufacture of oral-route preparations, the mentioned compoundsare blended with suitable additives, for example, vehicles such aslactose, mannitol, corn starch and crystalline cellulose; binders suchas cellulose derivatives, gum arabic and gelatin; disintegrators such ascarboxymethylcellulose calcium and lubricants such as magnesiumstearate, and formed into tablets, powders, granules, capsules and thelike. These solid preparations may further be coated with coating basessuch as hydroxypropylmethylcellulose phthalate,hydroxypropylmethylcellulose acetate succinate, cellulose acetatephthlate and methacrylate copolymers and formed into entericpreparations.

In the manufacture of non-oral route preparations, the compounds of theinvention may be combined, for example, with water, ethanol, glycerol orsurfactants which are routinely used in the pharmaceutical field andprepared into injection preparations; or combined with suppository basesto form suppositories.

The amounts of administration of the compounds (1) of the presentinvention vary depending on the age, body weight, state of the disease,aimed effects of the treatment, manner of administration, period ofadministration, etc. Generally, the compounds are administered inamounts of 1-2000 mg/day, preferably 10-300 mg/day, which are given asdivided in 1 to 3 times a day in the case of oral-route administration.

EXAMPLES

The present invention will hereinafter be described in more detail byway of examples, which however should not be construed as limiting theinvention thereto.

EXAMPLES 1-21

Preparation examples of aminoalcohol derivative (2), a preparatoryintermediate of the present invention, are shown below.

EXAMPLE 1 Preparation of4-dimethylamino-4-hydroxymethyl-4,5,6,7-tetrahydro-1-benzothiophene

The title compound was obtained via the following Steps 1-3.

Step 1: Preparation of4-amino-4-methoxycarbonyl-4,5,6,7-tetrahydro-1-benzothiophene

22.62 g of4,5,6,7-tetrahydro-spiro[1-benzothiophen-4,4'-imidazolidine]-2',5'-dionewas added to 300 ml of 20% NaOH solution and refluxed for 20 hours underheat. After cooling, the system was made weakly acidic with HCl, thenneutralized with an ammonia solution. After filtration, the filtrate wascondensed and dried, and the residue was added with 200 ml of methanoland 15 ml of conc. H₂ SO₄, followed by reflux under heat for 20 hours.After cooling, the solvent was removed under reduced pressure, and tothe residue was added water, and then sodium hydrogencarbonate formaking the system basic, followed by extracting with chloroform. Afterthe chloroform phase was dried, the solvent was removed to obtain 15.15g of the title compound as a pale yellow oily product.

The IR and MS data are shown below.

IR(neat)cm⁻¹ : 1720

MS(m/z): 211(M⁺)

The chemical formula is shown below. ##STR8##

Step 2: Preparation of4-dimethylamino-4-methoxycarbonyl-4,5,6,7-tetrahydro-1-benzothiophene

25 ml of formic acid containing 9.96 g of4-amino-4-methoxycarbonyl-4,5,6,7-tetrahydro-1-benzothiophene obtainedin Step 1 above was added with 9 ml of 35% formalin solution and heatedat 100° C. for 30 minutes. After cooling, the reaction mixture waspoured into ice-water, neutralized with sodium hydrogencarbonate andextracted with ether. The ether phase was washed with water and dried.The solvent was removed to obtain 7.80 g of the title compound as paleyellow crystals.

The melting point and MS are shown below.

Melting point: 72°-73° C.

MS(m/z): 239(M⁺)

The chemical formula is shown below. ##STR9##

Step 3: Preparation of4-dimethylamino-4-hydroxymethyl-4,5,6,7-tetrahydro-1-benzothiophene

65 ml of ether solution containing 7.77 g of4-dimethylamino-4-methoxycarbonyl-4,5,6,7-tetrahydro-1-benzothiopheneobtained in Step 2 was added to an ice-cooled suspension of aluminumlithium hydride (1.23 g) in ether, then stirred for 20 minutes at roomtemperature. The reaction mixture was added with 5% NaOH solution,filtrated to remove the insoluble matters, followed by drying theorganic phase.

The solvent was distilled off to obtain 6.58 g of the title compound ascolorless crystals.

The melting point, IR, MS and NMR data are shown below.

Melting point: 71°-72° C.

IR(KBr)cm⁻¹ : 3130

MS(m/z): 211(M⁺)

NMR(CDCl₃)δ: 1.47-1.58(1H,m), 1.71-1.98(3H,m), 2.21(6H,s), 2.74(2H,t),3.53(1H,d), 3.70(1H,d), 7.04(1H,d), 7.11(1H,d)

The chemical formula is shown below. ##STR10##

EXAMPLE 2 Preparation of4-dimethylamino-4-hydroxymethyl-4,5,6,7-tetrahydro-1-benzofuran

The title compound was obtained via the following Steps 1-3.

Step 1: Preparation of4-amino-4-methoxycarbonyl-4,5,6,7-tetrahydro-1-benzofuran

The title compound was obtained by following the procedure of Step 1 inExample 1 except that4,5,6,7-tetrahydro-spiro[1-benzofuran-4,4'-imidazolidine]-2',5'-dionewas used as the starting material.

Step 2: Preparation of4'-dimethylamino-4-methoxycarbonyl-4,5,6,7-tetrahydro-1-benzofuran

0.9 ml of 35% formalin solution was added to 10 ml of methanolcontaining 1.00 g of4-amino-4-methoxycarbonyl-4,5,6,7-tetrahydro-1-benzofuran obtained inStep 1 above. Subsequently, 10% palladium on carbon moistened with waterwas added to this solution. The reaction was continued for 3 hours in ahydrogen atmosphere, and then the insoluble matters were separated byfiltration through celite. The filtrate was dried over anhydrousmagnesium sulfate, and the solvent was removed to obtain 1.07 g of thetitle compound as a pale yellow oily product.

The IR data are shown below.

IR (neat ) cm⁻¹ : 1730

The chemical formula is shown below. ##STR11##

Step 3: Preparation of4-dimethylamino-4-hydroxymethyl-4,5,6,7-tetrahydro-1-benzofuran

The title compound was obtained by following the procedure of Step 3 inExample 1 except that4-dimethylamino-4-methoxycarbonyl-4,5,6,7-tetrahydro-1-benzofuranobtained in Step 2 was used as the starting material.

The melting point, IR, MS and NMR data are shown below.

Melting point: 91°-92° C.

IR (KBr) cm⁻¹ : 3200

MS (m/z): (CI) 196 (M⁺ +1)

NMR (CDCl₃) δ: 1.38˜1.50 (1H, m), 1.68˜2.00 (3H, m), 2.24(6H, s), 2.57(2H, t), 3.10˜3.40 (1H, brs), 3.47 (1H, d), 3.67 (1H, d), 6.43 (1H, d),7.25 (1H, d)

The chemical formula is shown below. ##STR12##

EXAMPLE 3 Preparation of4-(N-ethyl-N-methyl)amino-4-hydroxymethyl-4,5,6,7-tetrahydro-1-benzothiophene

The title compound was obtained by following the Steps 1-3 below.

Step 1: Preparation of4-N-acetylamino-4-methoxycarbonyl-4,5,6,7-tetrahydro-1-benzothiophene

10.0 g of 4-amino-4-methoxycarbonyl-4,5,6,7-tetrahydro-1-benzothiopheneand 5.27 g of triethylamine were dissolved in methylene chloride. 5.32 gof acetic anhydride was added thereto under ice-cooling, then thetemperature was returned to room temperature and the mixture was stirredfor 30 minutes.

After completion of the reaction, the reaction solution was diluted withethyl acetate, then washed with 1N HCl and saturated aqueous sodiumbicarbonate solution, and dried over anhydrous magnesium sulfate.Subsequently, the solvent was distilled off under reduced pressure toobtain 10.9 g of the title compound as pale brown crystals.

The IR data are shown below.

IR(KBr)cm⁻¹ : 3265, 1735, 1640

The chemical formula is shown below. ##STR13##

Step 2: Preparation of4-(N-acetyl-N-methyl)amino-4-methoxycarbonyl-4,5,6,7-tetrahydro-1-benzothiophene

To 120 ml of tetrahydrofuran suspended with 4.22 g of 60% sodium hydridewas added, under ice-cooling, 120 ml of tetrahydrofuran containing 17.70g of4-N-acetylamino-4-methoxycarbonyl-4,5,6,7-tetrahydro-1-benzothiophene asdissolved therein, followed by raising the temperature to roomtemperature while stirring for 20 minutes. Subsequently, 20 ml ofanhydrous tetrahydrofuran containing 8.9 ml of methyl iodide asdissolved was added thereto dropwise, followed by stirring for 3 hoursat 50° C.

After completion of the reaction, the reaction solution was condensedunder reduced pressure, then poured into ice-water, and extracted withethyl acetate. The ethyl acetate phase was washed with brine and driedover anhydrous magnesium sulfate, and then distilled off under reducedpressure to obtain 20.98 g of the title compound as a yellow oilyproduct.

The MS data are shown below.

Ms(m/z): 267(M⁺)

The chemical formula is shown below. ##STR14##

Step 3: Preparation of4-(N-ethyl-N-methyl)amino-4-hydroxymethyl-4,5,6,7-tetrahydro-1-benzothiophene

The title compound (oily product) was obtained by following theprocedure of Step 3 in Example 1 except that4-(N-acetyl-N-methyl)amino-4-methoxycarbonyl-4,5,6,7-tetrahydro-1-benzothiopheneobtained in Step 2 was used as the starting material.

The IR, MS and NMR data are shown below.

IR(neat)cm⁻¹ : 3440, 2935-2800

MS (m/z):(CI)226 (M⁺ +1)

NMR (CDCl₃) δ: 1.03 (3H, t), 1.49˜1.59 (1H, m), 1.68˜1.96 (3H, m), 2.20(3H, s), 2.23˜2.44 (2H, m), 2.74 (2H, t), 3.49 (1H, brs), 3.49 (1H, d),3.68 (1H, d), 7.03 (1H, d), 7.10 (1H, d) ##STR15##

EXAMPLE 4 Preparation of4-dimethylamino-1-methyl-4-hydroxymethyl-1,2,3,4-tetrahydroquinoline

The title compound was obtained via the following Steps 1-3.

Step 1: Preparation of4-amino-4-methoxycarbonyl-1-methyl-1,2,3,4-tetrahydroquinoline

The title compound was obtained by following the procedure of Step 1 inExample 1 except that1',2',3',4'-tetrahydro-1'-methyl-spiro[imidazolidine-4,4'-quinoline]-2,5-dionewas used as the starting material.

Step 2: Preparation of4-dimethylamino-4-methoxycarbonyl-1-methyl-1,2,3,4-tetrahydroquinoline

1.55 g of 4-amino-4-methoxycarbonyl-1-methyl-1,2,3,4-tetrahydroquinolineobtained in Step 1 was dissolved in 50 ml of dimethylformamide, thenadded with 2.24 g of methyl iodide and 2.14 g of anhydrous potassiumcarbonate and the mixture was stirred at room temperature for 15 hours.The reaction mixture was poured into water and extracted with ether. Theether phase was washed with water and dried with anhydrous magnesiumsulfate. The solvent was removed to obtain 1.51 g of the title compoundas pale yellow crystals.

The melting point, IR and MS data are shown below.

Melting point: 45°-46° C.

IR (KBr)cm⁻¹ : 1720, 1240, 755

MS (m/z): 248 (M⁺)

The chemical formula is shown below. ##STR16##

Step 3: Preparation of4-dimethylamino-4-hydroxymethyl-1,2,3,4-tetrahydroquinoline

The title compound was obtained by following the procedure of Step 3 inExample 1 except that4-dimethylamino-4-methoxycarbonyl-1-methyl-1,2,3,4-tetrahydroquinolineobtained in Step 2 was used as the starting material.

The melting point, IR, MS and NMR data are shown below.

Melting point: 104°-105° C.

IR(KBr)cm⁻¹ : 1500, 1105, 760

MS (m/z):(FAB)221 (M⁺ +1)

NMR (CDCl₃) δ: 1.71˜1.79(1H, m), 2.11˜2.22(1H, m), 2.25(3H, s), 2.27(3H,s), 2.55 (1H, bs), 2.88 (3H, s), 3.12˜3.28 (2H, m), 3.64(1H, d),3.74(1H, d), 6.59˜6.70(2H, m), 7.12˜7.18 (1H, m), 7.57 (1H, dd)

The chemical formula is shown below. ##STR17##

EXAMPLE 5 Preparation of4-dimethylamino-4-hydroxymethyl-2,3-dihydro-4H-1-benzopyran.HCl

The title compound was obtained by following the procedures of Steps 1-3in Example 1 except that2,3-dihydro-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione wasused as the starting material, and then converted to a hydrochloride.

The melting point, IR, MS and NMR data are shown below.

Melting point: 216°-217° C.

IR(KBr)cm⁻¹ : 1060

MS (m/z): 207 (M⁺)

NMR (CDCl₃) δ: 2.05˜2.30 (1H, m), 2.40˜2.60 (4H, m), 3.08 (3H, d),4.08˜4.17 (2H, m), 4.30˜4.40 (1H, m), 4.55˜4.70 (1H, m), 6.85˜6.94 (1H,m), 7.03˜7.15 (1H, m), 7.23˜7.35 (1H, m), 7.95˜8.05 (1H, m) ##STR18##

EXAMPLE 6 Preparation of4-dimethylamino-4-hydroxymethyl-2,3-dihydro-4H-1-benzothiopyran

The title compound was obtained by following the procedures of Steps 1-3in Example 1 except that2,3-dihydro-spiro[4H-1-benzothiopyran-4,4'-imidazolidine]-2',5'-dionewas used as the starting material.

The melting point, IR, MS and NMR data are shown below.

The melting point: 94°-95° C.

IR (KBr)cm⁻¹ : 2700˜3050

MS (m/z): 223 (M⁺)

NMR (CDCl₃) δ: 2.06˜2.23(3H, m),2.28(6H, s),2.87˜2.96(1H, m), 3.07˜3.17(1H, m), 3.71 (2H, dd), 7.03˜7.15 (3H, m), 7.71˜7.74(1H, m)

The chemical formula is shown below. ##STR19##

EXAMPLE 7 Preparation of5-dimethylamino-5-hydroxymethylcyclopenta[b]thiophene

The title compound was obtained by following the procedures of Steps 1-3in Example 1 except thatspiro[cyclopenta[b]thiophene-5,4'-imidazolidine]-2',5'-dione was used asthe starting material.

The IR, MS and NMR data are shown below.

IR(neat)cm⁻¹ : 2780-3070

MS (m/z): 196 (M⁺)

NMR (CDCl₃) δ: 2.27 (6H, s), 2.55˜2.74 (2H, m), 2.95(1H, d), 3.09(1H,d), 3.65 (2H, s), 6.76 (1H, d), 7.14˜7.15 (1H, m),

The chemical formula is shown below. ##STR20##

EXAMPLES 8-19

Compounds of the following nomenclature, chemical formulae, meltingpoints, IR, MS and NMR data were obtained by following the procedure ofExample 1.

EXAMPLE 8 4-Dimethylamino-4-hydroxymethyl-cyclopenta[b]thiophene##STR21## Melting point: 48°-49° C. IR (KBr) cm⁻¹ : 3175, 1465, 1040

MS (m/z):(FAB) 198(M⁺ +1)

NMR (CDCl₃) δ: 2.01˜2.11(1H, m), 2.18(6H, s), 2.57˜2.67(1H, m),2.87˜2.92 (2H, m), 3.00 (1H, brs), 3.57 (1H, d), 3.74(1H, d)

EXAMPLE 9 4-Dimethylamino-4-hydroxymethyl-cyclohepta[b]thiophene.HCl##STR22## Melting point: 165° C. IR(KBr) cm⁻¹ : 3200

MS (m/z):(CI)226(M⁺ +1)

NMR (CDCl₃) δ: 1.42˜1.96(4H, m),2.14˜2.25(2H, m), 2.56(3H, d), 2.77˜2.89(1H, m), 3.10˜3.22 (1H, m), 3.74(1H, dd), 4.10 (1H, dd), 5.95˜6.05 (1H,m), 7.33 (1H, d), 7.44 (1H, d) 9.76˜9.86 (1H, brs)

EXAMPLE 10 5-Dimethylamino-5-hydroxymethyl-5,6,7,8-tetrahydroquinoline##STR23## Melting point: 125°-126° C. IR(KBr) cm⁻¹ : 3130

MS (m/z): (CI) 207 (M⁺ +1)

NMR (CDCl₃) δ: 1.61˜2.03(4H, m), 2.22(6H, s), 2.75˜2.79(3H, m), 3.54(1H, d), 3.76 (1H, d), 7.12 (1H, dd), 7.96 (1H, dd), 8.40 (1H, dd)

EXAMPLE 11 1-Dimethylamino-1-hydroxymethyl-cycloheptabenzene ##STR24##

Oily product

IR(neat)cm⁻¹ : 3450, 2935-2785

MS (m/z):(CI)220(M⁺ +1)

NMR (CDCl₃) δ: 1.34˜1.45(1H, m), 1.52˜1.80(4H, m), 1.85˜2.04 (2H, m),2.25 (6H, s), 2.82˜2.86 (2H, m), 3.74(1H, d), 3.81 (1H, d), 7.08(1H, d),7.15(1H, dt), 7.21 (1H, dt), 7.76 (1H, d)

EXAMPLE 126-Chloro-4-dimethylamino-4-hydroxymethyl-2,3-dihydro-4H-1-benzopyran##STR25## Melting point: 107°-108° C. IR (KBr)cm⁻¹ : 3400, 1485, 1070

MS (m/z):(FAB)242 (M⁺ 30 1)

NMR (CDCl₃) δ: 1.71 (1H, m), 2.21 (1H, m), 2.23 (6H, s), 2.81 (1H, brs),3.67 (1H, d), 3.78 (1H, d), 4.17 (2H, m), 6.76 (1H, d), 7.09 (1H, dd),7.54 (1H, d)

EXAMPLE 134-Dimethylamino-6-fluoro-4-hydroxymethyl-2,3-dihydro-4H-1-benzopyran##STR26## Melting point: 100°-103° C. IR (KBr) cm⁻¹ : 3050˜2800, 1490,1460

MS (m/z):(CI)226(M⁺ +1)

NMR (CDCl₃) δ: 1.69 (1H, ddd), 2.16˜2.28 (1H, m), 2.23 (6H, s), 2.60(1H, brs), 3.68 (1H, d), 3.78 (1H, d), 4.06˜4.23 (2H, m), 6.77 (1H, dd),6.86 (1H, ddd), 7.29 (1H, dd)

EXAMPLE 144-Dimethylamino-4-hydroxymethyl-6-methoxy-2,3-dihydro-4H-1-benzopyran##STR27## Melting point: 90°-91° C. IR(KBr)cm⁻¹ : 3075˜2775, 1580, 1500

MS (m/z): (CI) 238 (M⁺ +1),

NMR (CDCl₃) δ: 1.70(1H, ddd), 2.17˜2.28 (1H, m), 2.24(6H, s), 2.55 (1H,brs), 3.64˜3.81 (2H, m), 3.76 (3H, s), 4.06˜4.20 (2H, m), 6.71˜6.79 (2H,m), 7.12 (1H, dd)

EXAMPLE 154-Dimethylamino-4-hydroxymethyl-6-methyl-2,3-dihydro-4H-1-benzopyran.HCl##STR28## Melting point: 110°-111° C. IR(KBr) cm⁻¹ : 3300, 1500, 1230

MS (m/z): (FAB) 222 (M⁺ +1)

NMR (CDCl₃) δ: 1.71(1H, m), 2.22(1H, m), 2.23(6H, s), 2.27(3H, s) 2.59(1H, brs), 3.70 (1H, d), 3.79 (1H, d), 4.14 (2H, m), 6.72 (1H, d), 6.95(1H, dd), 7.34 (1H, d)

EXAMPLE 164-Dimethylamino-4-hydroxymethyl-2,2-dimethyl-2,3-dihydro-4H-1-benzopyran##STR29## Melting point: 84°-85° C. IR(KBr)cm⁻¹ : 3120

MS (m/z) : (CI) 236 (M⁺ +1)

NMR (CDCl₃) δ: 1.27(3H, s), 1.39 (3H, s), 1.58(1H, d), 2.10(1H, d),2.15(6H, s), 3.26˜3.46 (1H, brs), 3.76 (2H, s), 6.81 (1H, dd), 6.92 (1H,ddd), 7.15 (1H, ddd), 7.59 (1H, dd)

EXAMPLE 17 6-Chloro-4-dimethylamino-4-hydroxymethyl-2,3-dihydro-4H-1-benzothiopyran ##STR30## Melting point: 88°-89° C. IR (KBr)cm⁻¹ :3200, 1470, 1080

MS (m/z): (FAB) 258 (M⁺ +1)

NMR (CDCl₃) δ:2.12(2H, m), 2.26(6H, s), 2.29(1H, brs),2.89(1H, m),3.10(1H, m), 3.63 (1H, d), 3.71 (1H, d), 7.05 (2H, m), 7.74 (1H, m)

EXAMPLE 184-Dimethylamino-4-hydroxymethyl-6-methoxy-2,3-dihydro-4H-1-benzothiopyran##STR31## Melting point: 116°-117° C. IR (KBr)cm⁻¹ : 3450, 1470, 1290

MS (m/z): (FAB) 254 (M⁺ +1)

NMR (CDCl₃) δ: 2.06 (1H, m), 2.19 (1H, m), 2.26 (6H, s), 2.36 (1H, brs),2.85 (1H, m), 3.08 (1H, m), 3.64 (1H, d), 3.70 (1H, d), 3.76 (3H, s),6.71 (1H, dd), 7.03 (1H, d), 7.36 (1H, d)

EXAMPLE 194-Dimethylamino-4-hydroxymethyl-6-methyl-2,3-dihydro-4H-1-benzothiopyran##STR32## Melting point: 84°-85° C. IR (KBr)cm⁻¹ : 3200, 1480, 1080

MS (m/z): (FAB) 238 (M⁺ +1)

NMR (CDCl₃) δ: 2.08 (1H, m), 2.20 (1H, m), 2.27 (6H, s), 2.29 (3H, s),2.88 (1H, m), 3.10 (1H, m), 3.66 (1H, d), 3.73 (1H, d), 6.92 (1H, dd),7.02 (1H, dd), 7.55 (1H, d)

EXAMPLE 20 Preparation of4-dimethylamino-4-hydroxymethyl-2,3-dihydro-4H-1-benzothiopyran-1-oxide

The title compound was obtained via the following procedure.

248 mg of 70% m-chloroperbenzoic acid was added to a 20 ml of methylenechloride solution containing 222 mg of4-dimethylamino-4-hydroxymethyl-2,3-dihydro-4H-1-benzothiopyrandissolved therein, and stirred at room temperature for 30 minutes. Thereaction solution was washed with 5% aqueous sodium thiosulfatesolution, saturated sodium bicarbonate solution and brine in this order,then dried over anhydrous magnesium sulfate. The solvent was removedunder reduced pressure, and the crystals were recrystallized from asolvent mixture of ethyl acetate and isopropyl ether. 53 mg of the titlecompound was obtained as colorless crystals. ##STR33## Melting point:132°-133° C. IR(KBr)cm⁻¹ : 3245, 1070, 1000

MS (m/z): (CI) 240 (M⁺ +1)

NMR (CDCl₃) δ: 1.88(1H, m), 2.26(6H, s), 2.40(1H, dd), 2.85(1H, m), 3.01(1H, m), 3.24 (1H, m), 3.59 (1H, d), 3.73 (1H, d), 7.43 (1H, dt), 7.53(1H, dt), 7.75 (1H, dd), 7.90 (1H, dd)

EXAMPLE 21 Preparation of4-dimethylamino-4-hydroxymethyl-2,3-dihydro-4H-1-benzothiopyran-1,1-dioxide

The title compound was obtained via the following procedure.

10 g of 4-dimethylamino-4-hydroxymethyl-2,3-dihydro-4H-1-benzothiopyranobtained in Example 6 were suspended in 100 ml of water, to which 50 mlof an aqueous solution of 20 g of potassium peroxomonosulfate was addedwhile stirring under ice cooling. After allowing to react for 1 hour, 3NNaOH solution was added thereto for neutralizing the mixture, followedby extraction with ether. After the ether phase was dried with anhydrousmagnesium sulfate, the solvent was condensed to obtain 5.73 g of thetitle compound as colorless crystals. ##STR34## Melting point: 137°-138°C. IR(KBr) cm⁻¹ : 1290, 1130, 760

MS (m/z): 255 (M⁺)

NMR (CDCl₃) δ: 2.00(1H, brs), 2.25(6H, s), 2.38(1H, ddd), 2.80 (1H,ddd), 3.33 (1H, ddd), 3.62 (1H, ddd), 3.82 (2H, s), 7.40˜7.65 (2H, m),7.85 (1H, dd), 7.96 (1H, dd)

EXAMPLES 22-86

Preparation examples of trialkylamine derivative (1) of the presentinvention are shown below.

EXAMPLE 22 Preparation of4-dimethylamino-4-[(3,4,5-trimethoxybenzoyloxy)methyl]-4,5,6,7-tetrahydro-1-benzothiophene

15 ml of pyridine Containing 1.52 g of4-dimethylamino-4-hydroxymethyl-4,5,6,7-tetrahydro-1-benzothiopheneobtained in Example 1 was cooled with ice, and added with 1.82 g of3,4,5-trimethoxybenzoylchloride. The reaction mixture was then stirredat room temperature for 14 hours. The solvent was removed under reducedpressure, and the residue was poured into water, followed by extractingwith chloroform. The chloroform phase was washed with water and dried.The solvent was removed under reduced pressure, and the residue wascrystallized from isopropyl ether to obtain 1.87 g of the title compoundas colorless crystals.

The melting point, IR, MS and NMR data are shown below.

Melting point: 82°-83° C.

IR(KBr)cm⁻¹ : 1710

MS(m/z): 405(M⁺)

NMR (CDCl₃) δ: 1.68˜1.80(1H, m), 1.90˜2.10 (3H, m), 2.27(6H, s), 2.77(2H, t), 3.87 (6H, s), 3.89 (3H, s), 4.41 (1H, d), 4.59 (1H, d), 7.04(1H, d), 7.14 (1H, d), 7.18 (2H, s)

Hydrochloride of the present product: colorless crystals

Melting point: 201°-202° C. (solvent for recrystalization: chloroform -isopropyl ether ) ##STR35##

EXAMPLES 23-28

Six kinds of compounds were obtained by following the procedure ofExample 22. The chemical formulae, melting points, IR, MS and NMR dataof these compounds are shown in Table 1.

                                      TABLE 1-1                                   __________________________________________________________________________     ##STR36##                                                                    Ex.                      Melting                                                                            MS    IR                                        No.                                                                              Q  m n R.sup.3                                                                            R.sup.4                                                                            R.sup.5                                                                            point °C.                                                                   (m/z) (cm.sup.-1)                                                                          NMR                                __________________________________________________________________________    23 -- 1 0 3-OCH.sub.3                                                                        4-OCH.sub.3                                                                        5-OCH.sub.3                                                                        138˜140                                                                      (Cl)  (KBr)  (CDCl.sub.3) δ: 2.43(6H,                                                s), 2.84˜2.89(1H, m),                                      392   2750˜3100                                                                      3.02(2H, d), 3.17(1H, d),                                                     3.82(6H, s),                                                     (M.sup.+  + 1)                                                                      1695   3.88(3H, s), 4.47(2H, s),                                                     6.78(1H, d)                                                                   7.13˜ 7.15(3H, m)            24 HCl                                                                              0 2 4-OCH.sub.3                                                                        H    H    194˜195                                                                      (Cl)  (KBr)  (CDCl.sub.3) δ:                                                         1.93˜2.12(3H, m),                                          346   2850˜3125                                                                      2.29˜2.33(1H, m),                                                       2.64(3H, d),                                                     (M.sup.+  + 1)                                                                      1710, 1605                                                                           2.80˜2.91(2H, m),                                                       3.00(3H, d),                                                                  3.87(3H, s), 4.89(1H, d),                                                     4.96(1H, d),                                                                  6.94˜6.98(2H, m),                                                       7.25(1H, d),                                                                  7.87(1H, d),                                                                  8.11˜8.14(2H,                __________________________________________________________________________                                               m)                             

                                      TABLE 1-2                                   __________________________________________________________________________                           Melting                                                                             MS    IR                                         Ex. No.                                                                            Q  m n R.sup.3                                                                            R.sup.4                                                                           R.sup.5                                                                         point °C.                                                                    (m/z) (cm.sup.-1)                                                                          NMR                                 __________________________________________________________________________    25   HCl                                                                              0 2 4-CO H   H 187˜191                                                                       (C1)  (KBr)  (CDCl.sub.3) δ:                                                         1.80˜2.36(4H, m),                                                       2.65(3H, d,)                                    OCH.sub.3        373   2400˜3100                                                                      2.70˜3.03(5H, m),                                                       3.95(3H, s),                                                     (M.sup.+  + 1)                                                                      1720   4.94(1H, d), 5.05(1H, d),                                                     7.27(1H, d),                                                                  7.88˜7.90(1H, m),                                                       8.12˜8.24(4H, m)              26   HCl                                                                              0 2 H    H   H 207   (Cl)  (KBr)  (CDCl.sub.3) δ:                                                         1.87˜2.20(3H, m),                                          316   1715   2.28˜2.38(1H, m),                                                       2.64(3H, d),                                                     (M.sup.+  + 1)                                                                             2.73˜3.07(5H, m),                                                       7.24˜7.28(1H, m),                                                       7.43˜7.53(2H, m),                                                       7.58˜ 7.65(1H, m),                                                      7.90˜7.94(1H, m),                                                       8.10˜8.16(2H, m)              27   HCl                                                                              0 2 4-Cl H   H 188˜189                                                                       (Cl)  (Kbr)  (CDCl.sub.3) δ:                                                         1.87˜2.36(4H, m),                                                       2.65(3H, m),                                                     350   1720   2.69˜2.94(2H, m),                                                       2.98(3H, d),                                                     (M.sup.+  + 1)                                                                             4.88(1H, d), 4.99(1H, d),                                                     7.25(1H, d),                                                                  7.43˜7.50(2H, m),                                                       7.89(1H, dd),                                                                 8.11˜8.18(2H, m),                                                       12.64˜12.87(1H, brs)          28   HCl                                                                              0 2 3-OCH.sub.3                                                                        4-OCH.sub.3                                                                       H 202˜203                                                                       (Cl)  (KBr)  (CDCl.sub.3) δ:                                                         1.90˜2.35(4H, m),                                                       2.66(3H, d),                                                     376   1720   2.70˜2.91(2H, m),                                                       2.98(3H, d),                                                     (M.sup.+  + 1)                                                                             3.96(6H, d), 4.87(1H, d),                                                     4.95(1H, d),                                                                  6.95(1H, m), 7.22˜7.28(1H,                                               m),                                                                          7.58˜7.62(1H, m),                                                       7.83˜7.95(2H,                 __________________________________________________________________________                                              m)                              

EXAMPLES 29-34

Six kinds of compounds were obtained by following the procedure ofExample 22. The chemical formulae, melting points, IR, MS and NMR dataof these compounds are shown in Table 2.

                                      TABLE 2-1                                   __________________________________________________________________________     ##STR37##                                                                    Ex.                        Melting                                                                             MS    IR                                     No.                                                                              Q  Y m n R.sup.3                                                                            R.sup.4                                                                            R.sup.5                                                                            point °C.                                                                    (m/z) (cm.sup.-1)                                                                          NMR                             __________________________________________________________________________    29 HCl                                                                              0 0 2 3-OCH.sub.3                                                                        4-OCH.sub.3                                                                        5-OCH.sub.3                                                                        217˜219                                                                       401   (KBr)  (CDCl.sub.3) δ:                                                         2.35˜2.65(5H, m),                                          (M.sup.+)                                                                           1710, 1120                                                                           2.92˜2.98(3H, m),                                                       3.74(3H, s),                                                                  3.85(6H, s),                                                                  4.00˜4.50(2H, m),                                                       4.94(2H, dd), 6.96(1H, d),                                                    7.00˜                                                                   7.10(1H, m), 7.26(2H, s),                                                     7.30˜                                                                   7.40(1H, m),                                                                  8.00˜8.10(1H, m)          30 HCl                                                                              S 0 2 3-OCH.sub.3                                                                        4-OCH.sub. 3                                                                       5-OCH.sub.3                                                                        185˜186                                                                       417   (KBr)  (CDCl.sub.3) δ:                                                         2.43˜2.53(1H, m)                                           (M.sup.+)                                                                           2850˜3010                                                                      2.66(3H, d),                                                                  2.73˜2.79(1H, m),                                                1710, 1585                                                                           2.83˜2.97(1H, m),                                                       3.04(3H, d),                                                                  3.23˜3.32(1H, m),                                                       3.91(3H, s),                                                                  3.92(6H, s), 5.08(2H, dd),                                                    7.24˜7.35(5H, m),                                                       7.43(1H, d)                     __________________________________________________________________________

                                      TABLE 2-2                                   __________________________________________________________________________                                 Melting                                                                            MS   IR                                     Ex. No.                                                                            Q Y  m n R.sup.3                                                                            R.sup.4                                                                            R.sup.5                                                                            point °C.                                                                   (m/z)                                                                              (cm.sup.-1)                                                                         NMR                              __________________________________________________________________________    31   --                                                                              CH.sub.2                                                                         1 0 3-OCH.sub.3                                                                        4-OCH.sub.3                                                                        5-OCH.sub.3                                                                        105˜106                                                                      (Cl) (KBr) (CDCl.sub.3) δ:                                                         2.51(6H, s),                                                       386  1700  3.10(2H, d), 3.20(2H, d),                                          (M.sup.+  + 1)                                                                           3.83(3H, s), 3.89(3H, s),                                                     4.41(2H, s),                                                                  7.07˜7.21(4H, m)           32   --                                                                              CH.sub.2                                                                         1 0 4-OCH.sub.3                                                                        H    H    85˜86                                                                        (Cl) (KBr) (CDCl.sub.3) δ:                                                         2.49(6H, s),                                                       326  1700  3.09(2H, d), 3.18(2H, d),                                                     3.85(3H, s),                                                       (M.sup.+  + 1)                                                                           4.38(2H, s),                                                                  6.82˜6.90(2H, m),                                                       7.08˜7.20(2H, m),                                                       7.25˜7.83(2H, m)           33   --                                                                              CH.sub.2                                                                         1 0 4-Cl H    H    119˜120                                                                      (Cl) (KBr) (CDCl.sub.3) δ:                                                         2.48(6H, s), 3.08(2H, d),                                          330  2760˜3100                                                                     3.20(2H, d), 4.41(2H, s),                                          (M.sup.+  + 1)                                                                     1705,1100                                                                           7.07˜7.19(4H, m),                                                       7.32˜7.36(2H, m),                                                       7.69˜7.73(2H, m)           34   --                                                                              CH.sub.2                                                                         1 0 4-CO H    H    104˜105                                                                      (Cl) (KBr) (CDCl.sub.3) δ:                                                         2.49(6H, s), 3.09(2H, d),                      OCH.sub.3           354  1725,1710                                                                           3.22(2H, d), 3.94(3H, s),                                          (M.sup.+  + 1)                                                                           4.45(2H, s), 7.15(4H, s),                                                     7.82˜7.85(2H, m),                                                       8.02˜ 8.05(2H,             __________________________________________________________________________                                                 m)                           

EXAMPLE 35 Preparation of4-dimethylamino-4-[(3,4,5-trimethoxybenzyloxy)methyl]-4,5,6,7-tetrahydro-1-benzothiophene

15 ml of tetrahydrofuran containing 2.57 g of4-dimethylamino-4-hydroxymethyl-4,5,6,7-tetrahydro-1-benzothiophenobtained in Example 1 was added to an ice-cooled suspension of 60%sodium hydride (0.54 g) in tetrahydrofuran. 15 ml of tetrahydrofurancontaining 2.90 g of 3,4,5-trimethoxybenzyl chloride was further addedto the reaction mixture, followed by refluxing under heat for 24 hours.After cooling, the reaction mixture was poured into hydrochloric acidsolution, and washed with ether. The aqueous phase was added with asodium hydroxyde solution for making the system basic, followed byextracting with chloroform. After the chloroform phase was washed withwater and dried, the solvent was removed. The residue was purified bysilica gel column chromatography to obtain 2.79 g of the title compoundas a pale yellow oily product.

The melting point, IR, MS and NMR data are shown below.

IR(neat)cm⁻¹ : 2950, 1595

MS(m/z): 391(M⁺)

NMR (CDCl₃) δ: 1.70˜2.00(4H, m), 2.24(6H, s), 2.68˜2.76(2H, m), 3.54(1H, d), 3.59 (1H, d), 3.80 (6H, s), 3.82 (3H, s), 4.41 (1H, d), 4.49(1H, d), 6.46 (2H, s), 7.01 (1H, d), 7.15 (1H, d)

Hydrochloride of the present product: colorless crystals

Melting point: 172°-173° C. (ethanol - ethyl acetate)

The chemical formula is shown below. ##STR38##

EXAMPLES 36-47

Eleven kinds of compounds were obtained by following the procedure ofExample 35. The chemical formulae, melting points, IR, MS and NMR dataof these compounds are shown in Tables 3 and 4.

                                      TABLE 3                                     __________________________________________________________________________     ##STR39##                                                                    Ex.               Melting                                                                            MS    IR                                               No.                                                                              R.sup.3                                                                            R.sup.4                                                                            R.sup.5                                                                         Q  point °C.                                                                   (m/z) (cm.sup.-1)                                                                         NMR                                        __________________________________________________________________________    36 4-Cl H    H HCl                                                                              171˜172                                                                      (Cl)  (KBr) (CDCl.sub.3) δ:                                                         1.64˜1.85(2H, m),                                                       2.03˜2.19(1H, m),                                           336   2100˜3100                                                                     2.43˜2.60(4H, m),                                                       2.68˜3.05(5H, m), 3.65(1H, d),                              (M.sup.+  + 1)                                                                      1110  4.41(1H, d), 4.56(1H, d), 4.72(1H, d),                                        7.15˜7.35                                                               (5H, m), 7.84˜7.92(1H, m),                                              12.29˜12.56(1H, brs)                 37 4-OCH.sub.3                                                                        H    H HCl                                                                              163˜164                                                                      (Cl)  (KBr) (CDCl.sub.3) δ:                                                         164˜1.75(2H, m),                                                        2.04˜2.10(1H, m),                                           332   2850˜3100                                                                     2.47(3H, d), 2.52˜2.56(1H, m),                                          2.75˜2.90(2H, m), 3.01                                      (M.sup.+  + 1)                                                                      1610  (3H, d), 3.61(1H, d), 3.80(3H, s),                                            4.36(1H, d), 4.49(1H, d),                                                     4.69(1H, d), 6.85˜6.88(2H, m),                                          7.18˜7.26(3H, m),                                                       7.89(1H, d)                                38 3-OCH.sub.3                                                                        4-OCH.sub.3                                                                        H -- Oily (Cl)  (Neat)                                                                              (CDCl.sub.3) δ:                                                         1.65˜2.01(4H, m), 2.23(6H, s),                                          2.65˜2.75(2H,                                          Product                                                                            362   2750˜3100                                                                     m), 3.45˜3.60(2H, m), 3.82(3H,                                          s), 3.86(3H, s), 4.39(1H, d),                                     (M.sup.+  + 1)                                                                      1595  4.46(1H, d), 6.72˜6.85(3H, m),                                          7.00(1H, d), 7.12(1H, d)                   39 4-CH.sub.3                                                                         H    H -- Oily (Cl)  (Neat)                                                                              (CDCl.sub.3) δ:                                                         1.73˜1.93(4H, m), 2.23(6H, s),                                          2.32(3H, s),                                                 Product                                                                            316   2770˜2930                                                                     2.70˜2.72(2H, m), 3.54(2H, s),                                          4.38(1H, d),                                                      (M.sup.+  + 1)                                                                      1080  4.49(1H, d), 6.99˜7.16(6H, m),       40 H    H    H HCl                                                                              170˜172                                                                      (Cl)  (KBr) (CDCl.sub.3) δ:                                                         1.71˜1.77(2H, m),                                                       2.04˜2.13(1H, m),                                           302   2800˜3125                                                                     2.48(3H, d), 2.55˜2.61(1H, m),                                          2.69˜2.88(2H, m),                                           (M.sup.+  + 1)                                                                      2450˜2625                                                                     3.03(3H, d), 3.65(1H, d), 4.43(1H, d),                                        4.55(1H, d),                                                                  4.76(1H, d), 7.19(1H, d),                                                     7.29˜7.37(5H, m), 7.90(1H,           __________________________________________________________________________                                       d)                                     

                                      TABLE 4-1                                   __________________________________________________________________________     ##STR40##                                                                    Ex.                         Melting                                                                            MS    IR                                     No.                                                                              Q  Y  m n R.sup.3                                                                            R.sup.4                                                                            R.sup.5                                                                            point °C.                                                                   (m/z) (cm.sup.-1)                                                                          .sup.1 H-NMR                    __________________________________________________________________________    41 HCl                                                                              S  0 2 3-OCH.sub.3                                                                        4-OCH.sub.3                                                                        5-OCH.sub.3                                                                        91˜92                                                                        (EI)  (KBr)  (DMSO-d.sub.6) δ:                                                       2.35˜2.51(4H, m),                                          403   2850˜3000                                                                      2.68˜2.73(1H, m),                                                       2.92(3H, d),                                                     (M.sup.+)                                                                           1595, 1510                                                                           3.04˜3.21(2H, m),                                                       3.63(3H, s),                                                                  3.75(6H, s), 3.92(1H, d),                                                     4.17                                                                          (1H, d), 4.48(2H, dd),                                                        6.60(2H, s),                                                                  7.16˜7.30(3H, m),                                                       8.12(1H, d)                     42 -- CH.sub. 2                                                                        1 1 3-OCH.sub.3                                                                        4-OCH.sub.3                                                                        5-OCH.sub.3                                                                        Oily (EI)  (Neat) (CDCl.sub.3) δ:                                                         1.80˜2.02(2H, m),                                     Product                                                                            385   2930, 1590                                                                           2.41(6H, s),                                                                  2.57˜3.00(4H, m),                                          (M.sup.+)                                                                           1125   3.40(1H, d), 3.45(1H, d),                                                     3.83(9H,                                                                      s), 4.43(2H, s), 6.55(2H,                                                     s),                                                                           7.00˜7.10(4H, m)          43 1/2                                                                              CH.sub.2                                                                         1 0 3-OCH.sub.3                                                                        4-OCH.sub.3                                                                        5-OCH.sub.3                                                                        133˜138                                                                      (Cl)  (KBr)  (CDCl.sub.3) δ:                                                         2.37(6H, s), 2.93(2H, d),          (*)                           372   1445, 1125                                                                           3.09(2H, d), 3.46(2H, s),                                        (M.sup.+  + 1)                                                                      755    3.82(6H, s), 3.83(3H, s),                                                     4.43(2H, s), 6.53(2H, s),                                                     7.10˜714(4H, m)           44 -- CH.sub.2                                                                         1 0 4-CH.sub.3                                                                         H    H    Oily (Cl)  (Neat) (CDCl.sub.3) δ:                                                         2.33(3H, s), 2.34(6H, S),                                   Product                                                                            296   2800˜3050                                                                      2.92(2H, d), 3.06(2H, d),                                                     3.43(2H, s)                                                      (M.sup.+  + 1)                                                                      1520   4.44(2H, s),                                                                  7.10˜7.25(8H,             __________________________________________________________________________                                                  m)                               (*): Pamoic Acid                                                         

                                      TABLE 4-2                                   __________________________________________________________________________    Ex.                         Melting                                                                            MS   IR                                      No.                                                                              Q  Y  m n R.sup.3                                                                            R.sup.4                                                                            R.sup.5                                                                            point °C.                                                                   (m/z)                                                                              (cm.sup.-1)                                                                          .sup.1 H-NMR                     __________________________________________________________________________    45 HCl                                                                              CH.sub.2                                                                         0 2 3-OCH.sub.3                                                                        4-OCH.sub.3                                                                        5-OCH.sub.3                                                                        184˜187                                                                      (E1) (KBr)  (CDCl.sub.3) δ:                                                         1.72˜2.05(3H, m),                                           385  2300˜3050                                                                      2.45(3H, d),                                                                  2.70˜2.78(3H, m)                                            (M.sup.+)                                                                          1590,1115                                                                            3.11(3H, d),                                                                  3.64˜3.85(10H, m),                                                      4.38(1H, d), 4.53(1H, d),                                                     5.56(2H, s),                                                                  7.12˜7.40(3H, m),                                                       8.35(1H, d), 12.29(1H, brs)      46 HCl                                                                              CH.sub.2                                                                         0 1 3-OCH.sub.3                                                                        4-OCH.sub.3                                                                        5-OCH.sub.3                                                                        73˜74                                                                        (CI) (KBr) 3360                                                                           (CDCl.sub.3) δ:                                                         2.35˜2.53(2H, m),                                           371  2850˜3030                                                                      2.58(3H, d), 2.90(3H, d),                                         (M.sup.+)                                                                          1590   2.95˜3.16(2H, m),                                                       3.72(1H, d),                                                                  3.83(3H, s), 3.84(6H, s),                                                     4.30(1H, d), 4.44(1H, d),                                                     4.62(1H, d), 6.55(2H, s),                                                     7.26˜7.40(3H, m),                                                       7.99˜8.02(1H, m)           47 -- CH.sub.2                                                                         1 0 4-OCH.sub.3                                                                        H    H    Oily (Cl) (Neat) (CDCl.sub.3) δ:                                                         2.34(6H, s),                                                 Product                                                                            312  2780˜3070                                                                      2.91(2H, d), 3.07(2H, d),                                                     3.42(2H, s),                                                      (M.sup.+  + 1)                                                                     1090   3.78(3H, s), 4.41(2H, s),                                                     6.82˜6.85(2H, m),                                                       7.11˜7.24(6H,              __________________________________________________________________________                                                 m)                           

EXAMPLES 48-65

Compounds of the following nomenclature, chemical formulae, meltingpoints, IR, MS land NMR data were obtained by following the procedure ofExample 22.

EXAMPLE 484-Dimethylamino-4-[(3,4,5-trimethoxybenzoyloxy)methyl]-cyclopenta[b]thiophene.HCl##STR41## Melting point: 127°-129° C. IR(KBr)cm⁻¹ : 1715, 1335, 1130

MS (m/z): (CI) 392 (M⁺ +1)

NMR (CDCl₃) δ: 2.70˜2.92 (7H, m), 3.05˜3.20 (3H, m), 3.91 (3H, s), 3.97(6H, s), 4.77 (1H, d), 4.37 (1H, d), 7.26 (1H, d), 7.37 (1H, d), 7.45(2H, s)

EXAMPLE 494-Dimethylamino-4-[(3,4,5-trimethoxybenzoyloxy)methyl]-cyclohepta[b]thiophene.HCl##STR42## Melting point: 158°-159° C. IR(KBr)cm⁻¹ : 1710

MS (m/z):(CI)420(M⁺ +1)

NMR (DMSO-d₆) δ: 1.57˜2.03(4H, m), 2.25˜2.50 (2H, m), 2.67 (3H, d), 2.79(3H, d), 2.84˜2.96 (1H, m), 3.12˜3.26 (1H, m), 3.74 (3H, s), 3.87 (6H,s), 4.80 (1H, d), 4.87 (1H, d), 7.33(2H, s), 7.41 (1H, d), 7.67 (1H, d),10.60˜11.00(1H, brs)

EXAMPLE 504-(N-ethyl-N-methyl)amino-4-[(3,4,5-trimethoxybenzoyloxy)methyl]-4,5,6,7-tetrahydro-1-benzothiophene##STR43## Melting point: 75°-76° C. IR(KBr)cm⁻¹ : 3000˜2750, 1720, 1590

MS (m/z):(CI)420(M⁺ +1)

NMR (CDCl₃) δ: 0.99(3H, t), 2.32˜2.44(2H, m), 2.73˜2.79(2H, m), 3.88(3H, s), 3.89 (6H, s), 4.42 (1H, d), 4.55 (1H, d), 7.01 (1H, d), 7.13(1H, d), 7.19 (2H, s)

EXAMPLE 514-Dimethylamino-4-[(3,4,5-trimethoxyphenylacetoxy)-methyl]-4,5,6,7-tetrahydro-1-benzothiophene.HCl##STR44##

Amorphous

IR(KBr)cm⁻¹ : 1745, 1590

MS (m/z):(CI)420(M⁺ 1)

NMR (CDCl₃) δ: 1.72-2.10 (4H, m), 2.53 (3H, brs), 2.65˜2.93 (5H, m),3.72˜3.90 (11H, m), 4.56˜4.73 (2H, m), 6.61 (2H, s), 7.20 (1H, d), 7.80(1H, d), 12.41 (1H, brs)

EXAMPLE 524-Dimethylamino-4-[[3-(3,4,5-trimethoxyphenyl)propanoyloxy]methyl]-4,5,6,7-tetrahydro-1-benzothiophene.fumaricacid salt ##STR45## Melting point: 157°-158° C. IR (KBr)cm⁻¹ :2940˜2835, 1745, 1590

MS (m/z): (EI) 433 (M⁺)

NMR (DMSO-d₆) δ: 1.55˜1.92(4H, m), 2.14 (6H, s), 2.58˜2.78(6H, m), 3.61(3H, s), 3.73 (6H, s), 4.10 (1H, d), 4.31 (1H, d), 6.49 (2H, s), 6.61(2H, s), 7.02 (1H, d), 7.21 (1H, d)

EXAMPLE 534-Dimethylamino-4-[(3,4,5-trimethoxybenzoyloxy)methyl]-4,5,6,7-tetrahydro-1-benzofuran.maleicacid salt ##STR46## Melting point: 121°-122° C. IR (KBr)cm⁻¹ : 1730

MS (m/z):(CI)390(M⁺ +1)

NMR (DMSO-d₆) δ: 1.82˜2.26(4H, m), 2.52˜2.90 (8H, m), 3.15˜3.50 (2H,brs), 3.76 (3H, s), 3.85 (6H, s), 4.50 (1H, d), 4.87 (1H, d), 6.04 (2H,s), 6.72(1H, d), 7.25 (2H, s), 7.67(1H, d)

EXAMPLE 545-Dimethylamino-5-[(3,4,5-trimethoxybenzoyloxy)methyl]-5,6,7,8-tetrahydro-quinoline.HCl##STR47## Melting point: 197°-205° C. IR (KBr)cm⁻¹ : 1720

MS (m/z): (CI) 401 (M⁺ +1)

NMR (DMSO-d₆) δ: 1.82˜2.14(2H, m), 2.20˜2.40(2H, m), 2.54(3H, brs),2.85˜3.15 (5H, m), 3.74 (3H, s), 3.87 (6H, s), 4.80 (1H, d), 4.90 (1H,d), 4.00˜6.00 (2H, brs), 7.28 (2H, s), 7.50˜7.60 (1H, m), 8.58˜8.66 (1H,m), 8.92˜9.02 (1H, m), 11.76˜12.00(1H, brs)

EXAMPLE 551-Dimethylamino-1-[(3,4,5-trimethoxybenzoyloxy)methyl]cycloheptabenzene##STR48##

Oily product

IR(neat)cm⁻¹ : 2940-2785, 1720, 1590

MS (m/z): (CI)414(M⁺ +1)

NMR (CDCl₃) δ: 1.35˜1.55(1H, m), 1.60˜2.08(5H, m), 2.32(6H, s), 2.65(1H, ddd), 3.40 (1H, ddd), 3.83 (6H, s), 3.89 (3H, s), 4.61 (1H, d),4.77 (1H, d), 7.08˜7.15 (3H, m), 7.25 (2H, s), 7.51˜7.55 (1H, m)

EXAMPLE 562-Dimethylamino-2-[(3,4,5-trimethoxybenzoyloxy)methyl]-1,2,3,4-tetrahydronaphthalene.HCl##STR49## Melting point: 160°-162° C. IR(KBr) cm⁻¹ : 1710, 1590

MS (m/z): (EI) 399 (M⁺)

NMR (CDCl₃) δ: 2.42˜2.51(2H, m),2.80˜3.07(2H, m),2.96(6H, s), 3.13 (1H,d), 3.58 (1H, d), 3.92 (3H, s), 3.94 (6H, s), 4.47 (1H, d), 4.55 (1H,d), 7.08˜7.23 (4H, m), 7.33 (2H, s), 12.79 (1H, brs)

EXAMPLE 576-Chloro-4-dimethylamino-4-[(3,4,5-trimethoxybenzoyloxy)methyl]-2,3-dihydro-4H-1-benzopyran.HCl##STR50## Melting point: 205°-206° C. IR(KBr) cm⁻¹ : 1715, 1590, 1335

MS (m/z): (EI) 435 (M⁺)

NMR (CDCl₃) δ: 2.34 (1H, m), 2.48 (1H, m), 2.69 (3H, d), 3.01 (3H, d),3.91 (3H, s), 3.94 (6H, s), 4.19 (1H, m), 4.40 (1H, m), 5.02 (1H, d),5.09 (1H, d), 6.91 (1H, d), 7.28 (1H, dd), 7.37 (2H, s), 8.38 (1H, d)

EXAMPLE 584-Dimethylamino-6-fluoro-4-[(3,4,5-trimethoxybenzoyloxy)methyl]-2,3-dihydro-4H-1-benzopyran.HCl##STR51## Melting point: 193°-195° C. IR(KBr) cm⁻¹ : 3015˜2835, 1715,1595

MS (m/z): (EI) 419 (M⁺)

NMR (CDCl₃) δ: 2.27˜2.36(1H, m), 2.39˜2.53(1H, m), 2.67(3H, d), 3.02(3H, d), 3.91 (3H, s), 3.93 (6H, s), 4.18 (1H, ddd), 4.32˜4.42 (1H, m),5.02 (1H, d), 5.12 (1H, d), 6.93 (1H, dd), 7.06 (1H, ddd), 7.35 (2H, s),8.19 (1H, dd), 13.25 (1H, brs)

EXAMPLE 594-Dimethylamino-6-methoxy-4-[(3,4,5-trimethoxybenzoyloxy)methyl]-2,3-dihydro-4H-1-benzopyran.HCl##STR52## Melting point: 194°-196° C. IR (KBr) cm⁻¹ : 1720, 1590, 1505

MS (m/z): (EI) 431 (M⁺)

NMR (CDCl₃) δ: 2.19˜2.40 (2H, m), 2.60 (3H, d), 3.06 (3H, d), 3.88 (3H,s), 3.91 (9H, s), 4.11˜4.22 (1H, m), 4.25˜4.35 (1H, m), 5.19 (2H, s),6.84˜6.94 (2H, m), 7.31 (2H, s), 7.92 (1H, d) 13.17 (1H, brs)

EXAMPLE 604-Dimethylamino-6-methyl-4-[(3,4,5-trimethoxybenzoyloxy)methyl]-2,3-dihydro-4H-1-benzopyran.HCl##STR53## Melting point: 205°-206° C. IR(KBr) cm⁻¹ : 1715, 1505, 1330

MS (m/z): (EI) 415 (M⁺)

NMR (CDCl₃) δ: 2.34 (3H, s), 2.37 (2H, m), 2.63 (3H, d), 3.01 (3H, d),3.91 (3H, s), 3.93 (6H, s), 4.16 (1H, m), 4.33 (1H, m), 5.09 (1H, d),5.14 (1H, d), 6.85 (1H, d), 7.13 (1H, dd), 7.35 (2H, s), 8.06 (1H, d)

EXAMPLE 614-Dimethylamino-2,2-dimethyl-4-[(3,4,5trimethoxybenzoyloxy)methyl]-2,3-dihydro-4H-1-benzopyran##STR54## Melting point: 114°-115° C. IR(KBr)cm⁻¹ : 1720

MS (m/z) : (EI) 429 (M⁺)

NMR (CHCl₃) δ:1.35(3H, s), 1.37(3H, s), 1.94(1H, d), 2.16(1H, d), 2.24(6H, s), 3.89 (6H, s), 3.90 (3H, s), 4.46 (1H, d), 4.56 (1H, d), 6.81(1H, dd), 6.93 (1H, dt), 7.15 (1H, ddd), 7.26 (2H, s), 7.60 (1H, dd)

EXAMPLE 626-Chloro-4-dimethylamino-4-[(3,4,5-trimethoxybenzoyloxy)methyl]-2,3-dihydro-4H-1-benzothiopyran.HCl##STR55## Melting point: 193°-194° C. IR (KBr) cm⁻¹ : 1715, 1330, 1215

MS (m/z): (EI) 451 (M⁺)

NMR (CDCl₃) δ: 2.55(1H, m), 2.73(3H, brs),2.81(1H, m), 2.98(1H, m), 3.03(3H, brs), 3.25 (1H, m), 3.91 (3H, s), 3.94 (6H, s), 4.96 (1H, d), 5.04(1H, d), 7.19 (1H, d), 7.26 (1H, dd), 7.33 (2H, s), 8.58 (1H, d)

EXAMPLE 634-Dimethylamino-6-methoxy-4-[(2,3,4-trimethoxybenzoyloxy)methyl]-2,3-dihydro-4H-1-benzothiopyran.HCl##STR56## Melting point: 189°-190° C. IR(KBr) cm⁻¹ : 1720, 1240, 1130

MS (m/z): (EI) 447 (M⁺)

NMR (CDCl₃) δ:2.44(1H, m), 2.63 (3H, d), 2.71(1H, m), 2.89(1H, m) 3.08(3H, d), 3.25 (1H, m), 3.90 (8H, s), 3.91 (3H, s), 3.94 (3H, s), 5.07(1H, d), 5.17 (1H, d), 6.88 (1H, dd), 7.13 (1H, d), 7.26 (2H, s), 8.08(1H, d)

EXAMPLE 644-Dimethylamino-6-methyl-4-[(3,4,5-trimethoxybenzoyloxy)methyl]-2,3-dihydro-4H-1-benzothiopyran.HCl##STR57## Melting point: 191°-192° C. IR(KBr) cm⁻¹ : 1720, 1335, 1130

MS (m/z): (EI) 431 (M⁺)

NMR (CDCl₃) δ:2.38 (3H, s), 2.49 (1H, m), 2.65 (3H, d), 2.71 (1H, m),2.93 (1H, m), 3.03 (3H, d), 3.24 (1H, m), 3.91 (3H, s), 3.92 (6H, s),5.02 (1H, d), 5.10 (1H, d), 7.11 (2H, m), 7.29 (2H, m), 8.29 (1H, m)

EXAMPLE 654-Dimethylamino-1-methyl-4-[(3,4,5-trimethoxybenzoyloxy)methyl]-1,2,3,4-tetrahydroquinoline##STR58## Melting point: 85°-86° C. IR (KBr) cm⁻¹ : 1715, 1330, 1125

MS (m/z): (EI) 414(M⁺)

NMR (CDCl₃) δ:1.88˜2.05 (1H, m), 2.16˜2.35 (1H, m), 2.32 (6H, s), 2.88(3H, s), 3.15˜3.32 (2H, m), 3.86 (6H, s), 3.89 (3H, s), 4.42 (1H, d),4.67 (1H, d), 6.61˜6.71 (2H, m), 7.10˜7.17 (1H, m), 7.19 (2H, s),7.56(1H, dd)

EXAMPLE 66 Preparation of4-dimethylamino-4-[(3,4,5-trimethoxybenzoyloxy)methyl]-2,3-dihydro-4H-1-benzothiopyran-1-oxide

The title compound was obtained via the following procedure.

1.13 g of4-dimethylamino-4-[(3,4,5-trimethoxybenzoyloxy)methyl]-2,3-dihydro-4H-1-benzothiopyran.HClobtained in Example 30 was dissolved in 110 ml of methylene chloride, towhich 525 mg of metachloroperbenzoic acid (70%) was added, followed bystirring for 10 minutes. The reaction mixture was added with saturatedaqueous sodium bicarbonate solution, and was subjected to separation.The methylene chloride phase was condenced, and purified through asilica gel column to obtain 739 mg of the title compound as colorlesscrystals.

The melting point, IR, MS and NMR data are shown below.

Melting point: 146°-148° C.

IR (KBr) cm⁻¹ : 1710, 1330, 1220, 1125, 1045

MS (m/z): (EI) 433 (M⁺)

NMR (CDCl₃) δ: 2.03(1H, ddd), 2.34(6H, s), 2.85˜3.15(2H, m), 3.32 (1H,ddd), 3.84 (6H, s), 3.88 (3H, s), 4.40 (1H, d), 4.46 (1H, d), 7.02 (2H,s), 7.46 (1H, ddd), 7.55 (1H, ddd), 7.80 (1H, dd), 8.00 (1H, dd)

The chemical formula is shown below. ##STR59##

EXAMPLE 67 Preparation of4-dimethylamino-4-[(3,4,5-trimethoxybenzoyloxy)methyl]-2,3-dihydro-4H-1-benzothiopyran-1,1-dioxide

The title compound was obtained via the following procedure.

1.13 g of4-dimethylamino-4-[(3,4,5-trimethoxybenzoyloxy)methyl]-2,3-dihydro-4H-1-benzothiopyran.HClobtained in Example 30 was added with 11 ml of 30% hydrogen peroxide and11 ml of acetic acid, and stirred for 20 hours at room temperature. Thereaction solution was neutralized, extracted with methylene chloride,and purified through a silica gel column to obtain 165 mg of the titlecompound as colorless crystals.

Melting point: 152° C.

MS (m/z):(E1)449(M+)

IR(KBr)cm⁻¹ : 1715, 1305, 1220, 1135, 1130, 1000

NMR (CDCl₃) δ: 2.32 (6H, s), 2.44˜2.64 (1H, m), 2.85˜3.03 (1H, m),3.29˜3.48 (1H, m), 3.53˜3.74 (1H, m), 3.83 (6H, s), 3.86 (3H, s), 4.55(2H, s), 7.00 (2H, s), 7.48 (1H, ddd), 7.58 (1H, ddd), 7.88 (1H, dd),7.97 (1H, dd) ##STR60##

EXAMPLES 68-86

The compounds of the following nomenclature, chemical formulas, meltingpoints, IR, MS and NMR were obtained according to the procedure ofExample 35.

EXAMPLE 684-Dimethylamino-4-[(3,4,5-trimethoxybenzyloxy)methyl]cyclopenta[b]thiophene##STR61##

Oily pruduct

IR(neat)cm⁻¹ 1460, 1235, 1125

MS (m/z):(CI)378(M⁺ +1)

NMR (CDCl₃) δ: 2.07˜2.30(1H, m), 2.21 (6H, s), 2.49˜2.71 (1H, m),2.80˜2.94(2H, m), 3.51 (1H, d), 3.59(1H, d), 3.80(6H, s), 3.82 (3H, s),4.48 (2H, s), 6.49 (2H, s), 6.98 (1H, d), 7.16(1H, d)

EXAMPLE 694-Dimethylamino-4-[(3,4,5-trimethoxybenzyloxy)methyl]cyclohepta[b]thiophene.HCl##STR62## Melting point: 107°-109° C. IR (KBr) cm⁻¹ : 1150

MS (m/z): (CI) 406 (M⁺ +1)

NMR (DMSO-d₆) δ: 1.45˜1.97 (4H, m), 2.17˜2.35 (2H, m), 2.55 (3H, d),2.75 (3H, d), 2.75˜2.90 (1H, m), 3.09˜3.23 (1H, m), 3.64 (3H, s), 3.77(6H, s), 3.79 (1H, d), 4.13 (1H, d), 4.47 (1H, d), 4.53 (1H, d), 6.64(2H, s), 7.37 (1H, d), 7.49(1H, d), 10.00˜10.20 (1H, brs)

EXAMPLE 704-(N-ethyl-N-methyl)amino-4-[(3,4,5-trimethoxybenzyloxy)methyl]-4,5,6,7-tetrahydro-1-benzothiophene.fumaricacid salt ##STR63## Melting point: 135°-137° C. IR (KBr) cm⁻¹ :3000˜2475, 1700, 1595

MS (m/z): (EI) 405 (M⁺)

NMR (DMSO-d₆) δ: 0.99 (3H, t), 1.70˜1.98 (4H, m), 2.33 (3H, s) 2.38˜2.61(2H, m), 2.66˜2.75 (2H, m), 3.59˜3.76 (11H, m), 4.33˜4.44 (2H, m), 6.55(2H, s), 6.59 (2H, s), 7.13 (1H, d), 7.25 (1H, d)

EXAMPLE 714-Dimethylamino-4-[(3,4,5-trimethoxybenzyloxy)methyl]-4,5,6,7-tetrahydro-1-benzofuran##STR64##

Oily product

IR(neat)cm⁻¹ : 1130

MS (m/z):(CI)376(M⁺ +1)

NMR (CDCl₃) δ: 1.58˜2.00(4H, m), 2.30(6H, s), 2.51(2H, m), 3.48 (1H, d),3.57 (1H, d), 3.80 (6H, s), 3.83 (3H, s), 4.47 (2H, s), 6.50 (2H, s),6.51 (1H, d), 7.23 (1H, d)

EXAMPLE 725-Dimethylamino-5-[(3,4,5-trimethoxybenzyloxy)methyl]-5,6,7,8-tetrahydroquinoline##STR65##

Oily product

IR(neat)cm⁻¹ : 1130

MS (m/z):(EI)386(M⁺)

NMR (CDCl₃) δ: 1.80˜2.00(4H, m), 2.22 (6H, s), 2.83˜2.93 (2H, m) 3.50(1H, d), 3.58 (1H, d), 3.78 (6H, s), 3.82 (3H, s), 4.33 (1H, d), 4.41(1H, d), 6.39 (2H, s), 7.11 (1H, dd), 8.03 (1H, dd), 8.38 (1H, dd)

EXAMPLE 731-Dimethylamino-1-[(3,4,5-trimethoxybenzyloxy)methyl]cycloheptabenzene.HCl##STR66## Melting point: 103°-107° C. IR (KBr) cm⁻¹ : 3320, 2940, 1595

MS (m/z): (EI)399(M⁺)

NMR (CDCl₃) δ:1.45˜1.80(2H, m), 1.84˜2.03 (2H, m), 2.12˜2.24(1H, m) 2.54(3H, d), 2.47˜2.63 (1H, m), 2.64˜2.75(1H, m), 3.03 (3H, d), 3.11˜3.25(1H, m), 3.74 (1H, d), 3.83 (3H, s), 3.85 (6H, s), 4.43 (1H, d),4.62˜4.73 (2H, m), 6.56 (2H, s), 7.14(1H, d), 7.25˜7.32 (1H, m),7.37˜7.45(1H, m), 8.23(1H, d)

EXAMPLE 742-Dimethylamino-2-[(3,4,5-trimethoxybenzyloxy)methyl]-1,2,3,4-tetrahydronaphthalene.fumaricacid salt ##STR67## Melting point: 144°-146° C. IR(KBr)cm⁻¹ : 2950˜2840,1715, 1680

MS (m/z): (EI) 385 (M⁺)

NMR (DMSO-d₆) δ: 1.83˜2.03 (2H, m), 2.50 (6H, s), 2.59˜2.88 (2H, m),2.82 (1H, d), 3.00 (1H, d), 3.44˜3.53 (2H, m), 3.64 (3H, s), 3.75 (6H,s), 4.41 (2H, s), 6.55 (2H, s), 6.62 (2H, s), 7.07 (4H, s)

EXAMPLE 754-Dimethylamino-4-[(3,4,5-trimethoxybenzyloxy)methyl]-2,3-dihydro-4H-1-benzopyran. 2-(4-hydroxybenzoyl)benzoic acid salt ##STR68## Melting point:140°-141° C. IR(KBr) cm⁻¹ : 1660, 1130

MS (m/z) : (CI) 388 (M⁺ +1)

NMR (DMSO-d₆) δ: 1.90˜2.00(1H, m), 2.06˜2.16 (1H, m),2.16(6H, s),3.10˜3.60 (1H, brs), 3.62 (3H, s), 3.68 (1H, d), 3.70 (6H, s), 3.72 (1H,d), 4.08˜4.26 (2H, m), 4.33 (1H, d), 4.40 (1H, d), 6.50 (2H, s), 6.74(1H, dd), 6.78˜6.90 (3H, m), 7.07˜7.15 (1H, m), 7.34 (1H, dd), 7.44˜7.54(3H, m), 7.57˜7.73(2H, m), 7.95(1H, dd), 10.30˜10.70(1H, brs)

EXAMPLE 766-Chloro-4-dimethylamino-4-[(3,4,5-trimethoxybenzyloxy)methyl]-2,3-dihydro-4H-1-benzopyran.HCl##STR69## Melting point: 176°-177° C. IR (KBr) cm⁻¹ : 1595, 1510, 1130

MS (m/z): (EI) 421 (M⁺)

NMR (CDCl₃) δ: 2.25(1H, m), 2.53(3H, d), 2.61(1H, m), 3.06(3H, d), 3.83(3H, s), 3.85 (6H, s), 3.87 (1H, d), 3.97 (1H, m), 4.35 (1H, m), 4.41(1H, d), 4.59 (1H, d), 4.70 (1H, d), 6.53 (2H, s), 6.84 (1H, d), 7.23(1H, dd), 8.35 (1H, d)

EXAMPLE 774-Dimethylamino-6-fluoro-4-[(3,4,5-trimethoxybenzyloxy)methyl]-2,3-dihydro-4H-1-benzopyran. 2-(4-hydroxybenzoyl)benzoic acid salt ##STR70## Melting point:162°-163° C. IR(KBr) cm⁻¹ : 3455, 1660, 1590

MS (m/z):(EI)405(M⁺)

NMR (DMSO-d₆) δ: 1.84˜1.95(1H, m), 2.09˜2.22 (1H, m), 2.18(6H, s), 3.63(3H, s), 3.64˜3.72 (2H, m), 3.71 (6H, s), 4.08˜4.22 (2H, m), 4.35 (1H,d), 4.41 (1H, d), 6.50 (2H, s), 6.74˜6.84 (3H, m), 6.92˜7.02 (1H, m),7.23˜7.35(2H, m), 7.46˜7.52 (2H, m), 7.60(1H, ddd), 7.68 (1H, ddd), 7.95(1H, dd), 10.36 (1H, brs)

EXAMPLE 784-Dimethylamino-6-methoxy-4-[(3,4,5-trimethoxybenzyloxy)methyl]-2,3-dihydro-4H-1-benzopyran.HCl##STR71## Melting point: 76°-79° C. IR(KBr)cm⁻¹ : 1595, 1500

MS (m/z): (EI) 417 (M⁺)

NMR (CDCl₃) δ: 2.17(1H, ddd),2.48 (3H, d), 2.57˜2.66(1H, m), 3.08(3H,d), 3.81˜3.99 (14H, m), 4.23˜4.32 (1H, m), 4.39 (1H, d), 4.64˜4.75 (2H,m), 6.53 (2H, s), 6.79 (1H, d), 6.86 (1H, dd), 7.88 (1H, d), 12.66 (1H,brs)

EXAMPLE 794-Dimethylamino-6-methyl-4-[(3,4,5-trimethoxybenzyloxy)methyl]-2,3-dihydro-4H-1-benzofuran.HCl##STR72## Melting point: 75°-76° C. IR(KBr)cm⁻¹ : 1590, 1510, 1225

MS (m/z): (EI) 401 (M⁺)

NMR (CDCl₃) δ: 2.20 (1H, m), 2.34 (3H, s), 2.47 (3H, d), 2.62 (1H, m),3.08 (3H, d), 3.83 (3H, s), 3.85 (6H, s), 3.88 (1H, d), 3.96 (1H, m),4.30 (1H, m), 4.39 (1H, d), 4.64 (1H, d), 4.72 (1H, d), 6.54 (2H, s),6.77 (1H, d), 7.07 (1H, dd), 8.05(1H, d)

EXAMPLE 804-Dimethylamino-2,2-dimethyl-4-[(3,4,5-trimethoxybenzyloxy)methyl]-2,3-dihydro-4H-1-benzopyran##STR73##

Oily product

IR(neat)cm¹ : 1590, 1130, 760

MS (m/z): (EI) 415 (M⁺)

NMR (CDCl₃) δ: 1.23(3H, s), 1.42(3H, s), 1.96(1H, d), 2.07 (1H, d), 2.18(6H, s), 3.51 (1H, d), 3.76 (1H, d), 3.81 (6H, s), 3.83 (3H, s), 4.44(2H, s), 6.51 (2H, s), 6.79 (1H, dd), 6.90 (1H, ddd), 7.13 (1H, ddd),7.50 (1H, dd)

EXAMPLE 816-Chloro-4-dimethylamino-4-[(3,4,5-trimethoxybenzyloxy)methyl]-2,3-dihydro-4H-1-benzothiopyran.HCl##STR74## Melting point: 135°-136° C. IR (KBr) cm⁻¹ : 1590, 1465, 1130

MS (m/z): (EI) 437 (M⁺)

NMR (CDCl₃) δ: 2.16 (1H, m), 2.55 (3H, d), 2.96 (2H, m), 3.02 (1H, m),3.09 (3H, d), 3.81 (1H, d), 3.83 (3H, s), 3.86 (6H, s), 4.40 (1H, d),4.54 (1H, d), 4.69 (1H, d), 6.54 (2H, s), 7.11 (1H, d), 7.20 (1H, dd),8.59 (1H, d)

EXAMPLE 824-Dimethylamino-6-methoxy-4-[(3,4,5-trimethoxybenzyloxy)methyl]-2,3-dihydro-4H-1-benzothiopyran.HCl##STR75## Melting point: 91°-92° C. (KBr) cm⁻¹ : 1120

MS(m/z): (EI)433(M⁺)

(DMSO-d₆) δ: 2.30˜2.50 (4H, m), 2.64˜2.76 (1H, m), 2.92 (3H, d),2.97˜3.19 (2H, m), 3.64 (3H, s), 3.75 (6H, s), 3.77 (3H, s), 3.91 (1H,d), 4.19 (1H, d), 4.45 (1H, d), 4.51 (1H, d), 6.61 (2H, s), 6.91 (1H,dd), 7.14 (1H, d), 7.78 (1H, d), 10.95˜11.08(1H, brs)

EXAMPLE 834-Dimethylamino-6-methyl-4-[(3,4,5-trimethoxybenzyloxy)methyl]-2,3-dihydro-4H-1-benzothiopyran.HCl##STR76## Melting point: 136°-137° C. IR(KBr)cm⁻¹ : 1590, 1120, 1100

MS (m/z): (EI) 417 (M⁺)

NMR (CDCl₃) δ:2.12˜2.30 (1H, m), 2.38 (3H, s), 2.48 (3H, d), 2.79˜2.95(1H, m), 2.94˜3.10 (2H, m), 3.10 (3H, d), 3.81(1 H, d), 3.84 (3H, s),3.86 (6H, s), 4.37 (1H, d), 4.59(1 H, d), 4.71 (1H, d), 6.54 (2H, s),7.05 (2H, s), 8.32(1H, s)

EXAMPLE 844-Dimethylamino-1-methyl-4-[(3,4,5-trimethoxybenzyloxy)methyl]-1,2,3,4-tetrahydroquinoline##STR77##

Oily product

IR(neat)cm⁻¹ : 1505, 1330, 1130

MS (m/z):(EI)400(M⁺)

NMR (CDCl₃) δ: 2.00˜2.19(2H, m), 2.29(6H, s), 2.85(3H, s), 3.10˜3.27(2H, m), 3.64 (2H, s), 3.80 (6H, s), 3.82 (3H, s), 4.36 (1H, d), 4.43(1H, d), 6.46 (2H, s), 6.57˜6.69 (2H, m), 7.08˜7.14 (1H, m), 7.47 (1H,dd)

EXAMPLE 854-Dimethylamino-4-[(3,4,5-trimethoxybenzyloxy)methyl]-2,3-dihydro-4H-1-benzothiopyran-1-oxide##STR78##

Oily product

IR(neat)cm⁻¹ : 1590, 1460, 1130

MS (m/z): (CI) 420 (M⁺ +1)

NMR (CDCl₃) δ: 2.11 (1H, ddd), 2.26 (6H, s), 2.88 (1H, ddd), 3.05 (1H,ddd), 3.30 (1H, ddd), 3.50 (1H, d), 3.67 (1H, d), 3.77 (6H, s), 3.81(3H, s), 4.22 (1H, d), 4.35 (1H, d), 6.29 (2H, s), 7.41 (1H, ddd), 7.51(1H, ddd), 7.74(1H, dd), 7.91 (1H, dd)

EXAMPLE 86 4-Dimethylamino-4-[(3,4,5-trimethoxybenzyloxy)methyl]-2,3-dihydro-4H-1-benzothiopyran-1,1-dioxide ##STR79##

Amorphous

IR(KBr)cm⁻¹ : 1590, 1290, 1130

MS (m/z): (EI) 435 (M⁺)

NMR (CDCl₃) δ: 2.24(6H, s), 2.52(1H, ddd), 2.77 (1H, ddd), 3.33(1H,ddd), 3.61 (1H, d), 3.78 (1H, d), 3.85˜3.80 (1H, m), 3.79 (6H, s), 3.82(3H, s), 4.25 (1H, d), 4.37 (1H, d), 7.26 (2H, s), 7.44 (1H, ddd), 7.52(1H, ddd), 7.80 (1H, dd), 7.93 (1H, dd)

EXAMPLE 87 Formulation of Preparation Example 1

    ______________________________________                                        Compound of Example 22                                                                             20 g                                                     Lactose             315 g                                                     Corn starch         125 g                                                     Crystalline cellulose                                                                              25 g                                                     ______________________________________                                    

The ingredients indicated above were blended to form a uniform mixture,to which 200 ml of 7.5% aqueous hydroxypropylcellulose solution wasadded, and then passed an extruder equipped with a screen of 0.5 mm indiameter to prepare granules. Immediately thereafter, the granules wererounded with a marumerizer and dried to obtain a granule preparation.

EXAMPLE 88 Formulation of Preparation Example 2

    ______________________________________                                        Compound of Example 29                                                                              20 g                                                    Lactose               100 g                                                   Corn starch           36 g                                                    Crystalline cellulose 30 g                                                    Carboxymethylcellulose calcium                                                                      10 g                                                    Magnesium stearate     4 g                                                    ______________________________________                                    

The ingredients indicated above were blended to form a uniform mixture,and prepared into tablets each weighing 200 mg with a single-shottableting machine equipped with a pestle having a diameter of 7.5 mm.

EXAMPLE 89 Formulation of Preparation Example 3

    ______________________________________                                        Compound of Example 41 100 mg                                                 Sodium acetate          2 mg                                                  Acetic acid (to adjust pH to 5.8)                                                                    suitable amount                                        Purified water         suitable amount                                        Total:                  10 ml/vial                                            ______________________________________                                    

The above formulation was prepared into an injection preparation by amethod known per se.

TEXT EXAMPLES Test 1 Accelerating Action of Gastrointestinal Motility

The test was performed according to the method of Itoh et al. (Am. J.Dig. Dis. 22, 117-124, 1977). In detail, laparotomy was made tomale-dogs (body weight: 9-10 kg) under anesthesia with Nembutal (30mg/kg, i.v.). Force transducers (F-121S, manufactured by Star MedicalCo.) were implanted in the direction so that the contraction of circularmuscle could be monitored on serosa of gastric body, gastric antrum(about 3 cm proximal to the annular pylorus), duodenum and jejunum. Inaddition, a silicone tube was inserted from the right external carotidartery, and the tube was indwelled in the superior vena cava. Thetransducers and the silicone tube were subcutaneously exteriorized outof the body.

The dog was submitted to the test with consciousness and withoutrestraint after about 3 weeks from the operation.

The contractile signals from each transducer were amplified with anamplifier (RTA-1200; manufactured by Nippon Koden Co.), and recordedwith a recording apparatus and a computer. The test compounds weredissolved in the saline and intravenously administered (0.5 ml/kg) tothe dog through a silicone tube about 10 minutes after the terminationof the gastrointestinal inter digestive migrating contractions(IMC) inthe antrum.

Evaluation Method

Contracle signals amplified as analog voltage were converted to digitalsignals, which were integrated to calculate the motor activity. Thequantity of work which allows to maintain the 1 V variation in voltagefor 6 seconds was counted as 1 unit, and the moter index in the periodof 30 minutes after the administration of the test compound wasobtained. The thus calculated moter index was compared with the moterindex obtained after the saline was administered.

The results are shown in Table 5.

                  TABLE 5                                                         ______________________________________                                                                    Moter Index                                       Test Compounds  Dose (mg/Kg)                                                                              Ratio*                                            ______________________________________                                        Example 22      3           2.2                                               Example 29      3           1.7                                               Example 30      3           1.6                                               Example 35      3           1.2                                               Example 41      3           2.1                                               Example 49      3           1.3                                               Example 69      3           1.6                                               Example 75      3           1.2                                               Control compound                                                                              3           1.0                                               (trimebutine maleate)                                                         ______________________________________                                         *The moter index of the control compound = 1                             

Test 2 Toxicity Test

Groups of 4-5 week old ICR mice, each group consisting of 6 mice, wereprovided for the test. The compounds obtained in Examples 22, 29 and 41were respectively suspended in 5% gum arabic and each was orallyadministered to the mice at a dose of 500 mg/kg. The mice were observedfor 1 week. No death was found in any of the dosage groups.

INDUSTRIAL APPLICABILITY

Since the compounds of present invention have the activity ofaccelerating the gastrointestinal contraction, in other words, theyimprove the gastrointestinal motility significantly, while they are verysafe, they have the utility in the medical field of treating thegastrointestinal disorders and the like.

We claim:
 1. A trialkylamine derivative represented by the formula (1)or a pharmaceutically acceptable salt thereof: ##STR80## wherein R¹ andR² may be the same or different from each other and each representslower alkyl;R³, R⁴ and R⁵ may be the same or different from one anotherand each represents hydrogen, lower alkyl, lower alkoxy, loweralkoxycarbonyl or halogen; R⁶ and R⁷ may be the same or different fromeach other and each represents hydrogen or lower alkyl; R⁸ representshydrogen, lower alkyl, lower alkoxy or halogen; X represents oxygen,sulfur or --CH═CH--; Y represents oxygen, sulfur or methylene; Zrepresents --OCO(CH₂)_(p) ˜ or --OCH₂ (CH₂)_(p) ˜ (wherein p representsa number of 0 to 4 and symbol ˜ represents the linkage with a benzenering); m is zero and n is 1,2 or 3, provided that the case where m is 0,n is 1 or 2, R¹ and R² represent each methyl, X represents --CH═CH--, Yrepresents --CH₂ --, and Z represents --O--CO˜ is excluded.
 2. Anaminoalcohol derivative represented by the formula (2) or a saltthereof: ##STR81## wherein R¹ and R² are the same or different from eachother and each represents lower alkyl,R⁶ and R⁷ may be the same ordifferent from each other and each represents hydrogen or lower alkyl,R⁸ represents hydrogen, lower alkyl, lower alkoxy or halogen, Xrepresents oxygen, sulfur or --CH═CH--; Y represents oxygen, sulfur ormethylene; m is zero and n is 1, 2 or 3, provided that the case where Xrepresents --CH═CH--, Y represents --CH₂ --, m is 0 and n is 1 or 2 isexcluded.
 3. A pharmaceutical composition as an ameliorant forgastrointestinal motility containing, as its active ingredient, aneffective amount of a trialkylamine derivative represented by theformula (1) or a pharmaceutically acceptable salt thereof: ##STR82##wherein R¹ and R² may be the same or different from each other and eachrepresents lower alkyl;R³, R⁴ and R⁵ may be the same or different fromone another and each represents hydrogen, lower alkyl, lower alkoxy,lower alkoxycarbonyl or halogen; R⁶ and R⁷ may be the same or differentfrom each other and each represents hydrogen or lower alkyl; R⁸represents hydrogen, lower alkyl, lower alkoxy or halogen; X representsoxygen, sulfur or --CH═CH--; Y represents oxygen, sulfur or methylene; Zrepresents --OCO(CH₂)_(p) ˜ or --OCH₂ (CH₂)_(p) ˜ (wherein p representsa number of 0 to 4 and symbol ˜ represents the linkage with a benzenering); m is zero and n is 1, 2 or 3, provided that the case where m is0, n is 1 or 2, R¹ and R² represent each methyl, X represents --CH═CH--,Y represents --CH₂ --, and Z represents --O--CO˜ is excluded; and apharmaceutically acceptable carrier.
 4. A compound as claimed in claim 1which is4-dimethylamino-4-[(3,4,5-trimethoxybenzoyloxy)methyl]-4,5,6,7-tetrahydro-1-benzothiophene.5. The composition of claim 3 wherein the trialkylamine is4-dimethylamino-4-[(3,4,5-trimethoxybenzoyloxy)methyl]-4,5,6,7-tetrahydro-1-benzothiophene.